Pharmaceutical compositions comprising mixed salts of sulfoglycopeptides with metal and organic bases

ABSTRACT

An orally administrable pharmaceutical composition useful in the treatment of gastro-duodenal diseases comprises, as active component, an effective amount of a mixed salt whose anionic moiety is a sulfoglycopeptide polyanion and whose cationic moiety is an alkali or alkaline-earth metal cation and a nitrogencontaining organic cation derived from a base having spasmolytic and anti-cholinergic activity.

United States Patent Butti et al.

PHARMACEUTICAL COMPOSITIONS COMPRISING MIXED SALTS 0F SULFOGLYCOPEPTIDESWITH METAL AND ORGANIC BASES Inventors: Adriano Butti, Como; GiuseppePrino', Milan, both of Italy Assignee: Crinos Industria FarmacobiologicaSpA, Guardia, Italy Filed: Mar. 22, 1974 Appl. No.: 453,764

Foreign Application Priority Data Mar. 27, 1973 Italy 22212/73 US. Cl.424/177; 424/260; 424/265 Int. CL. A61K 37/00; AOIN 9/00; AOlN 9/22Field of Search 260/112 R, 112.5; 424/117,

References Cited UNITED STATES PATENTS 3/1965 Abramo et a1 424/17712/1965 Casadio 4/1969 Baldwin 424/177 1 H1969 Argoudelis et a1 424/1771 1 Dec. 16, 1975 3.518.243 6/1970 Butti et a1. v. 260/112 R FOREIGNPATENTS OR APPLICATIONS 2,031,401 2/1971 Germany 3.891 3/1966 FranceOTHER PUBLICATIONS Pellmont et al.: Chem. Abstr. 74:6396h (1971).Philips GLF Chem. Abstr. 7021181 lOj (I969). Notarianni et al.: Chem.Abstr. 732774555 (1970). Arnold et al.: Chem. Abstr. 73:76844f (1970).Voroshazy et 2112 Chem. Abstr. 75:133021c (1971). Prino et a1.: Chem.Abstr. 75:108340y (1971).

Primary ExaminerLewis Gotts Assistant ExaminerReginald .1. Suyat'Attorney, Agent, or FirmBrowdy and Neimark 57 I ABSTRACT 16 Claims, NoDrawings PHARMACEUTICAL COMPOSITIONS COMPRISING MIXED SALTS OFSULFOGLYCOPEPTIDES WITH METAL AND ORGANIC BASES BACKGROUND OF THEINVENTION 1. Field of the invention The present invention relates toorally administrable pharmaceutical compositions particularly useful inthe treatment of gastro-duodenal diseases. which comprise as activecomponents. mixed salts of polysulfuric esters of naturally occurringglycopeptides with metal and organic bases.

2. Description of the prior art The US. Pat. No. 3,518,243 discloses aprocess for sulfonating glycopeptides of animal origin. thus obtainingsulfoglycopeptides (hereinafter referred to as SGLP). This patent alsodiscloses that the alkali. alkaline-earth. and heavy metal salts ofSGLP. are useful as drugs. for instance in the treatment of inflammatorydiseases and particularly in the treatment of arthroses and gastriculcers. These salts. especially the alkalineearth metal salts. arehowever somewhat toxic and consequently special precautions are to betaken to reduce their toxity. when these salts are used for therepeuticpurposes.

In the copending U.S. patent applications Ser. No. 405.l78 and 405.179.filed Oct. 10. 1973, now US. Pat. No. 3.872.075. and assigned to thesame assignee as this application. there have been disclosed salts ofsulfoglycopeptides with metals and aminoacids and pharmaceuticalcompositions containing them. which salts are endowed withanti-inflammatory, cicatrizing. anti-secretory and anti-pepticproperties. These properties make such salts and their compositionsparticularly useful in the treatment of gastro-duodenal diseases. Thesalts compositions disclosed in the above identified patent applicationsare substantially nontoxic and present an anti-inflammatory activityhigher than that of the SGLP salts disclosed in the US. Pat. No.3.518.243. The salts and compositions disclosed in the foregoing patentapplications are however ineffective on the peripheral nervous systemand are consequently poorly active on the symptomatology of theaforementioned diseases, and particularly against the painful spasmwhich periodically accompany the gastro-duodenal diseases. So. forinstance, it is know that the sulfoglycopeptide sodium salt. whileactive in inhibiting both the experimentally-induced ulcers and theactivity of gastroproteases and the acidic secretion of gastic juice.does not alter however the intestinal contractility and is ineffectiveon the peripheral nervous system (see Prino et al., Eur. J. Pharmacol.l5. l99l26. I971; Prino et al.. Arzneim-Forsch. 2l. 9l8-92l. l97l; Prinoet al. Eur. J. Pharmacol. l7 279-282, I972; Prino et al.. Am. J. Dig.Dis.. 17. 863-867. 1972).

SUMMARY OF THE INVENTION It has now been found that pharmaceuticalcompositions comprising. as active component. an effective amount of awater-soluble salt. wherein the anionic moiety is a sulfoglycopeptidepolyanion and the cationic moiety is formed by:

a. a metal cation selected from the group consisting of the alkali andalkaline-earth metal cations; and

b. a nitrogen-containing organic cation derived from an organic basehaving spasmolytic and anti-cholinergic activities,

are extremely effective against gastro-duodenal diseases. while notsubstantially presenting any toxic activity.

The active components of the pharmaceutical compositons in accordancewith this invention and a process for their preparation have beendisclosed in our copending application Ser. No. 453.765 filed on Mar.22. 1974. now US. Pat. No. 3.900.458.

These salts have been found to synergistically combine theanti-secretory. anti-peptic and protective action shown bysulfoglycopeptides. with the spasmolytic and anti-secretory activityshown by the bases to such an extent that the amount of both SGLP andbase components present in the mixed salt is far lower than the amountof the same components when used separately. with a view to obtainingthe same therapeutic result. Remarkable importance is to be attached tosuch synergistic effect. if it is taken into account that drugs of thistype are often used in long-term treatments and that anti-cholinergicagents show at the doses currently used noticeable, generally undesiredside-effects.

It has further been found that the mixed salts in accordance with thisinvention are far less toxic than the corresponding amount of the basecontained in the same salt. Consequently it was not possible to obtainan evaluation for LD since at the maximum dose which was orallyadministrable to rats, a mortality ranging from 10 to l6% only dependingon the specific salt was obtained.

DESCRIPTION OF THE PREFERRED EMBODIMENTS As aforementioned. in thecourse of experimental tests relating to anti-secretory and anti-ulceractivity. a higher synergistic activity of the compositions of thisinvention in comparison with the compositions comprising the SGLP andbase. as separate components, has been shown. Particularly. thecompositions comprising those mixed salts which contain from about 5 toabout 20% by weight of base component were shown to effectively inhibitexperimentally-induced ulcers and secretion of acidic gastric juice to alarger extent then the sum of the activities shown by the base andsulfoglycopeptide when separately administered.

In the course of other tests it was shown that the specific activitiesof the salt components, such as the anti-peptic activity of thesulfoglycopeptide and the anti-cholinergic and spasmolytic activity ofthe bases. were not modified.

Preferred. although non-limiting examples of the aforementioned organicbases are: atropine. hyoscine. anisotropine and papaverine. Among themetal cations. sodium is particularly preferred.

As mentioned above. the compositions of this invention have been foundto be extremely effective in the treatment of gastro-duodenal diseases.In fact. in tests performed on laboratory animals. the compositions ofthis invention have proved to be active in the following:

a, inhibition of u.cer caused by pylorus ligature and restraint at adose of 20-200 mg/kg;

b. acidity inhibition of acid gastric secretion induced by ligature. ata dose of about 50 mg/kg'.

c. inhibition of acid gastric secretion induced by pentagastrine ug/kgadministered intravenously) at a dose of about IOOmg/kg;

3 d. inhibition of gastrointestinal motility induced by methacoline(Zmg/kg administered subcutaneously) at a dose of about 50mg./kg. Thefollowing pharmacological tests further illustrate the therapeuticproperties of the compositions in ac cordance with this invention.

PHARMACOLOGICAL TESTS In order to show the pharmacological activity ofthe SGLP mixed salt in accordance with this invention there are herebydisclosed. as non-limiting examples. some results obtained with theanisotropine-sodium salt of sulfoglycopeptide (SGLP/Na/anisotropine).which has been tested on rats in a number of pharmacological tests. incomparison with the results shown by anisotropine methylbromide(8-methyltropinium-bromide 3- 2propyl)pentanoate) and the sodium salt ofthe sulfoglycopeptide SGLP/ Na It has been found that theanisotropine-containing salt of sulfoglycopeptide is very slightly toxicto rat after oral administration; when expressed as anisotropinecontent. a remarkable decrease in this drug toxity is observed (Tablel).

A number of pharmacological tests have shown an enhancement of the mixedsalt activity over the single salt components this phenomenon isparticularly apparent in the treatment of ulcer caused by pylorusligature (Table ll). restraint ulcer (Table III), and the acidicsecretion of gastric juice (Table [V and V).

A number of different tests have shown that some SGLP and anisotropinepharmacological activities are maintained in the mixed salt: forinstance. the anisotropine activity on intestinal hypermotility inducedby a cholinergic stimulus (Table VI). or on the acetylcholine-inducedspasm in guinea pigs isolated ileus are quantitatively maintained in themixed salts; also the anti-peptic activity of SGLP is not altered by theanisotropine presence in the mixed salt (Table Vll).

TABLE I Acute toxity after oral administration to rats (which have beenkept under observation for 10 days) of SGLP sodium salt. anisotropinemethyl-bromide and anisotropine-sodium mixed salt of sulfoglycopeptide(containing 15.6% of anisotropine base).

Substance L and confidence limits SGLP/Na non-toxic at 4g/kgAnisotrnpine 794 (MN-92] mg/kg methyl-bromide SGLPlNa/Anisutrupinenon-toxic at 4g/kg TABLE II No. of Treatment oral Ulcer score InhibitionP rats dose mean SE 3) Saline HI ml/kg 1 l7 1- 0.3) 3t) SGLP/Na 35 mg/kg2.4M 10.39 24.3 NS 30 Anisotropine mg/kg 2 ()5 H38 35.] (HISmethylbromide -continued Nu. ol 'l'reatment oral L'lcer score InhibitionP rats tlusc mean t SE S 30 SGLP/Na! 3" mg/kg L25 1 u :x hlHi (HllllAnisutropine NOTE In score is mean! the .ucrngc \ziluc nl' arhitrarscores giwn in uhserwd ulcers SF =Stamlanl error P=Pruhabilit N5=Nnistatistical") significant TABLE III Inhibition of restraint-inducedulcer in rats after oral administration of SGLP sodium salt.anisotropine methylbromide and anisotropine-sodium mixed salt ofsulfoglycoppetide (containing 7.8% of anisotropine base).

N0. of Treatment oral dose Ulcer score Inhibition P rats dose mean t SE30 Saline mg/kg 3.30 t 0.28 3U SGLP/Na lilllmg/ltg 2.96 t 0.35 l0.4 NS30 Anisotropine mg/kg L96 10.30 40.6 (H1US 2S methylbromidi: SG LP/NaZUUmg/kg L16 3: ".28 (1| .8 ().(JU|

Anisutropini:

TABLE [V Effect on basal gastric secretion of rats which have beenorally administered with SGLP sodium salt, anisotropine methylbromideand anisotropine-sodium mixed salt of sulfoglycopeptide (containing15.6% of anisotropine base).

A. Acidity inhibition of ligature-induced gastric secretion No. ofTreatment oral HmEq/lh Inhibit. P

rats dose 1 24 Saline 2 ml/Kg l.3l 10.16 24 SGLP/Na 40 tug/kg 10.16 7.6NS 24 Anisotropine Ill mg/kg ((5 t 0.2 35.! NS me thylhromide 24 SGLP/Namg/kg 0.33 (HM 74.8 ().()Ul

Anisotropine B. Inhibition of the amount of gastric secretion afterligature lnhibition of acid gastric secretion induced by pentagastrine(8O ug/kg l.V.) in rats which have been orally administered with SGLPsodium salt. anisotropine methylbromide and anisotropine-sodium mixedsalt of sulfoglycopeptide (containing 7.8% of anisotropine base).

Activity of SGLP sodium salt, anisotropine methylbromide andanisotropine-sodium mixed salt of sulfoglycopeptide (containing l5.6% ofanisotropine base) on methacoline-induced gastrointestinal motility ofrats Zmg/kg so.)

No. of Treatment Oral Run of coal lnhih P rats dose suspension 4cm.)mean I SF.

2H Saline (no 5 ml/kg 54.97 t 1.2

methacoline 2U Saline 5 ml/kg 87.41 t l 9 solution 20 SGLP/Na 41; mg/kg83.48 1 2.4 4.5 NS Ill Anisotropine ll] mg/kg 521 t 2.7 40.4 [),ll()lmethylhromide 20 SGLP/Na 50 mg/kg 51.3 x 2.4 41.1 uu| Anisotropine TABLE VII Anti-peptic activity of, SGLP sodium salt. anisotropinemethylbromide and anisotropine-sodium mixed salt of sulfoglycopeptide(containing 7.8% of anisotropine base Pylorus ligature was maintainedfor hours and the treatment was started immediately after ligature.

No. of Treatment Oral Peptic lnhib. P

rats dose activity 9% ill. moles of tyrosine) Saline 2 ml/kg 62.5 i 5.420 SGLP/Na 80 mg/kg 37.7 r 5.6 39.7 ().()l 20 Anisotropine 8.8mg/kg 53.3I 7.2 l6.3 NS

methylhromide 2U SGLP/Na 88.8mg/kg 32.3 1- 4.6 48 3 (|.(IU|

Anisot ropine In order to be orally administered to human beings. thecomposition of this invention can be incorporated in any one of theseveral pharmaceutically acceptable carriers or coatings which are wellknown to those skilled in the art.

For instance. capsules having the following compostion can be prepared:

SGLP/NalAnisotropine mg 50.0 Lactose l'lh.4 Aerosil l i 2.4

Magnesium stearatc 1.2

(I I trade name of an impalpahlc silica An illustrative composition fortablets is as follows:

SGLP/Na/Anisotropinc mg 50.0 Avicell l2) 25M) Talc 8,3 Aerosil (I) 0.7

(3) Trade name of a microgranular cellulose.

Modifications and/or changes may he made by those skilled in the an tothe process and mixed salts according to this invention. withoutdeparting from the scope and spirit thereof.

What we claim is:

1. An orally administrablc pharmaceutical composition. comprising:

an amount effective for the treatment of gastroduodenal diseases of amixed salt. wherein the anionic moiety is a sulfoglycopeptide polyanionand the cationic moiety is:

a. a metal cation selected from the group consisting of the alkali andalkaline-earth metal cations. and

b. the cation of a nitrogen-containing organic base having spasmolyticand anticholinergic activities; and

a pharmaceutically acceptable carrier or coating.

2. The composition of claim 1. wherein the content of saidnitrogen-containing organic cation in said mixed Salt is 5 to 20% byweight.

3. The composition of claim 2. wherein said metal cation is sodium.

4. The composition of claim 2. wherein said base is atropine.

5. The composition of claim 2, wherein said base is hyoscine.

6. The composition of claim 2, wherein said base is anisotropine.

7. The composition of claim 2, wherein said base is papaverine.

8. The composition of claim 1 in unit dosage form 9. A composition inaccordance with claim 1, wherein said base is selected from the groupconsisting of atropine. hyoscine. anisotropine and papaverine.

10. A composition in accordance with claim 1, wherein said mixed salt ispresent in an anti-inflammatory. cicatrizing. anti-secretory oranti-peptic non-toxic amount.

11. A method for treating gastro-duodenal diseases comprisingadministering an amount effective for the treatment of gastro-duodenaldiseases of a mixed salt having. as the anionic moiety thereof. asulfoglycopeptide polyanion. and. as the cationic moiety thereof:

a. a metal cation selected from the group consisting of the alkali andalkaline-earth metal cations. and

b. the cation of a nitrogen-containing organic base having spasmolyticand anticholinergic activities.

12. A method in accordance with claim 11, wherein the mixed salt is inthe presence of a pharmaceutically acceptable carrier or coating.

13. A method in accordance with claim 11, wherein the content of saidnitrogen-containing organic cation in said mixed salt is about 5 toabout 20% by weight.

14. A method in accordance with claim 13, wherein said base is selectedfrom the group consisting of atro pine. hysocine. anisotropine andpapaverine.

15. A method in accordance with claim 11, wherein said mixed salt isadministered in an anti-inflammatory. cicatrizing. anti-secretory orantipeptic non-toxic amount.

16. A method in accordance with claim 14, wherein said metal cation issodium.

1. AN ORALLY ADMINISTRABLE PHARMACUETICAL COMPOSITION COMPRISING: ANAMOUNT EFFECTIVE FOR THE TREATMENT OF GASTRODUODENAL DISEASES OF A MIXEDSALT, WHEREIN THE ANIONIC MOIETY IS A SULFOGLYCOLPEPTIDE POLYANION ANDTHE CATIONIC MOIETY IS: A. A METAL CATION SELECTED FROM THE GROUPCONSISTING OF THE ALKALI AND ALKALINE-EARTH METAL CATIONS, AND B. THECATION OF A NITROGEN-CONTAINING ORGANIC BASE HAVING SPASMOLYTIC ANDANTICHOLINERGIC ACITIVITIES; AND A PHARMACEUTICALLY ACCEPTABLE CARRIEROR COATING.
 2. The composition of claim 1, wherein the content of saidnitrogen-containing organic cation in said mixed salt is 5 to 20% byweight.
 3. The composition of claim 2, wherein said metal cation issodium.
 4. The composition of claim 2, wherein said base is atropine. 5.The composition of claim 2, wherein said base is hyoscine.
 6. Thecomposition of claim 2, wherein said base is anisotropine.
 7. Thecomposition of claim 2, wherein said base is papaverine.
 8. Thecomposition of claim 1 in unit dosage form.
 9. A composition inaccordance with claim 1, wherein said base is selected from the groupconsisting of atropine, hyoscine, anisotropine and papaverine.
 10. Acomposition in accordance with claim 1, wherein said mixed salt ispresent in an anti-inflammatory, cicatrizing, anti-secretory oranti-peptic non-toxic amount.
 11. A method for treating gastro-duodenaldiseases comprising administering an amount effective for the treatmentof gastro-duodenal diseases of a mixed salt having, as the anionicmoiety thereof, a sulfoglycopeptide polyanion, and, as the cationicmoiety thereof: a. a metal cation selected from the group consisting ofthe alkali and alkaline-earth metal cations, and b. the cation of anitrogen-containing organic base having spasmolytic and anticholinergicactivities.
 12. A method in accordance with claim 11, wherein the mixedsalt is in the presence of a pharmaceutically acceptable carrier orcoating.
 13. A method in accordance with claim 11, wherein the contentof said nitrogen-containing organic cation in said mixed salt is about 5to about 20% by weight.
 14. A method in accordance with claim 13,wherein said base is selected from the group consisting of atropine,hysocine, anisotropine and papaverine.
 15. A method in accordance withclaim 11, wherein said mixed salt is administered in ananti-inflammatory, cicatrizing, anti-secretory or anti-peptic non-toxicamount.
 16. A method in accordance with claim 14, wherein said metalcation is sodium.